ALS Treatment Target Found With Help From Yeast

With the help of baker's yeast, a tiny one-celled organism, scientists in the US say they have found a "chink in the armor" of the currently incurable
disease Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig's disease. They suggest their finding offers a new target for therapies, bringing fresh
hope to patients with a devastatingly cruel disorder that robs them of the ability to move, speak and in the end, breathe.

The researchers write about their discovery in the 28 October online issue of Nature Genetics.

Co-senior author Aaron Gitler is an associate professor in the department of genetics at Stanford University School of Medicine in California. He says in a press
statement:

"Even though yeast and humans are separated by a billion years of evolution, we were able to use the power of yeast genetics to identify an unexpected
potential drug target for ALS."

Protein Clumps

Many disorders like ALS, Parkinson's and Alzheimer's that gradually destroy the brain, show a particular type of clumping or misfolding of proteins in the
cytoplasm of brain cells or neurons (the cytoplasm being the internal gel that holds the various components of cells). The protein clumping or misfolding is
thought either to cause or contribute to the disease.

"We are trying to figure out why these proteins aggregate in neurons in the brain and spinal cord, and what happens when they do," explains Gitler.

While the cause of ALS is not clear, recent studies suggest an RNA-binding protein called TDP-43 may play a role. In many people with ALS, the protein forms
clumps inside neurons of the spinal cord, and some people with ALS also have mutations in this protein.

The Value of a Yeast Model

Previous work by Gitler and another study author, Robert Farese Jr, a senior investigator at the Gladstone Institutes in San Francisco, California, shows it is
possible to mimic ALS in yeast by expressing TDP-43 at higher levels than normal: the result is the protein forms deadly clumps in the cytoplasm of the
yeast cells.

Gitler explains the value of the yeast model:

"In humans, the progression of the disease can take years before symptoms arise. But in yeast, we see protein clumping in the cytoplasm within two days and
the cells rapidly begin to die."

Having developed the yeast model, Gitler and Farese decided to see if changing the behavior of some of the other proteins in the cell could protect the yeast cells
from the clumping damage.

What They Found

After tinkering with various proteins in the yeast cells, the researchers eventually found blocking the production of a protein called Dbr1, an enzyme involved in
RNA processing, prevented the clumping that results from TDP-43 over-expression, allowing the cells to lead a normal existence.

Farese says they went about their search systematically: they made no prior assumptions about how TDP-43 injures cells, but instead "screened the whole yeast
genome to find genes that might prevent the toxicity".

He says his lab and Gitler's lab came to the same conclusion about Dbr1 independently.

They then tested and proved blocking Dbr1 worked by repeating the results in lab-cultured human nerve cells and in rat neurons over-expressing TDP-43.

Mopping Up Excess TDP-43

The researchers found that blocking Dbr1 causes a buildup of "lariats" in the cytoplasm. These are unwanted "loops" of RNA left over from coding DNA into
proteins. Dbr1 cuts open the loops to make it easier for the cellular clean up tools to take them away for disposal and recycling.

Blocking Dbr1 causes uncut lariats to accumulate, which appear to mop up the excess TDP-43 so it doesn't form clumps. The researchers proved this was the
case by creating lariats with a binding site for a fluorescent tracking protein.

First author Maria Armakola, also of the department of genetics at Stanford's School of Medicine, says normally TDP-43 stays in the nucleus, but in diseased cells
it collects in the cytoplasm and forms clumps.

"We developed a novel way to track where these lariats go in living cells, and we saw that when Dbr1 is missing, the lariats act as a sink to sequester TDP-
43," she explains.

Treatment Targets

The researchers aren't exactly sure what is causing the cells to die in ALS: is it because the defective TDP-43 pulls essential RNA molecules that should be busy
helping to read DNA to make proteins out of the nucleus into the cytoplasm, or because the defectiive TDP-43 is not working as it should, which is to bind to
RNA in the nucleus? Perhaps it's a bit of both, they suggest.

Whichever it is, because of the promising results from the yeast, human and rodent cell experiments, the researchers recommend more studies should now
investigate the potential for blocking Dbr1, or creating artificial lariats to snare the defective TDP-43, as a potential target for drugs to treat
ALS.

Armakola says they now want to look at what happens when you block Dbr1 in flies, worms and rodents.

"We're also interested in identifying small molecule inhibitors of Dbr1," she adds.

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